The P.I., Dr. Mark Savellano, is a biomedical engineer with experience in contrast agent design, molecular imaging, and photodynamic therapy (PDT). His long-term goal is to obtain a tenure track position that will allow him to build an independent cancer research program in these emerging interdisciplinary fields. During an initial two-year mentored phase, Dr. Savellano will receive critical training from his sponsors in various aspects of cancer research. Dr. Keith Paulsen, a highly experienced biomedical engineering professor at Dartmouth College, has established a world-class alternative breast cancer imaging modalities research program. Under Dr. Paulsen's guidance, Dr. Savellano will learn about optical imaging hardware and tomographic reconstruction methods, and in return, he will develop contrast agents for optical breast cancer imaging. To augment his contrast agent design skills, he will learn antibody engineering methods from Dr. Mary Jo Mulligan-Kehoe, a well respected biomedical researcher at Dartmouth. Dr. Mulligan-Kehoe will also provide guidance in tumor biology and anti-angiogenesis research. Given the many parallels between optical contrast agents and photosensitizer drug delivery agents, Dr. Savellano will investigate how optical imaging can be combined with PDT. Dr. Savellano has extensive expertise in PDT research and will be a key member of a dedicated group of PDT scientists at Dartmouth. To assure clinical relevance, Dr. Peter Kaufman, an experienced clinical oncologist in breast and ovarian cancer, will mentor Dr. Savellano on aspects of molecular-targeted cancer therapies. The proposed project will develop new strategies to improve the efficacy of photoimmunodetection (PID) and photoimmunotherapy (PIT) in the diagnosis and treatment of cancer. In Aim 1, novel fluorochrome-photosensitizer immunoconjugates (FPICs) will be developed that should enable concomitant PID and PIT. In Aim 2, multi-targeting strategies using FPICs targeted to multiple epitopes will be developed to boost FPIC uptake levels. In Aim 3, antibody engineering will be used to construct FPICs that efficiently dequench via lysosomal degradation, which should improve FPIC performance by reducing quenching effects. FPICs will be targeted to erbB receptors and the vascular endothelial growth factor receptor-2. These receptors are ideal targets for PID/PIT since they are often overexpressed and/or overactivated in many cancers, especially aggressive high-risk breast cancers.